Probiotics for Prevention of Neratinib-Induced Diarrhea in Breast Cancer Patients

Breast cancer patients treated with the tyrosine kinase inhibitor (TKI) Neratinib often experience severe diarrhea, leading to treatment interruptions, dose reductions, or discontinuation. Emerging evidence highlights the role of gut microbiota in drug metabolism and gastrointestinal toxicity. Probiotics have been proposed as a potential intervention to modulate gut microbiota and mitigate diarrhea; however, their efficacy in preventing Neratinib-induced diarrhea remains inconclusive. This randomized, double-blind, placebo-controlled clinical trial aims to evaluate the efficacy and safety of probiotics in preventing diarrhea in HER2-positive breast cancer patients receiving Neratinib. The study will also explore the impact of probiotics on gut microbiota composition and potential microbiome-mediated mechanisms that may enhance treatment adherence and therapeutic outcomes. Participants will be randomly assigned in a 1:1 ratio to either a probiotics group or a placebo group. Both groups will receive prophylactic loperamide in accordance with the dosing schedule recommended by the U.S. Food and Drug Administration (FDA) for the prevention of Neratinib-associated diarrhea, ensuring consistency with the approved prescribing information. Participants will receive treatment for a total of six weeks, corresponding to two treatment cycles. Metagenomic sequencing and targeted metabolomics will be performed on stool samples to investigate gut microbial composition and metabolic changes. Additional analyses will assess the association between gut-derived metabolites and immune cell activation, aiming to elucidate potential interactions among gut microbiota, metabolites, and immune responses. Sun Yat-sen Memorial Hospital will serve as the coordinating center for this planned multicenter trial. Currently, it is the only active site, and additional participating centers will be added progressively as they are initiated.